Obstructive sleep apnea (OSA) affects 3-5% of the adult population. Its consequences include sleepiness, reduced productivity and a low quality of life. OSA is causally associated with hypertension and may lead to type 2 diabetes. Based on existing evidence and our preliminary data, we hypothesize that chronic intermittent hypoxia (IH), a major pathogenic factor in OSA, increases central adrenergic activity. This, in turn, alters the hypothalamic control of glucose metabolism and leads to a diabetes-like condition. We further hypothesize that relevant central changes in the hypothalamus are mediated by noradrenergic and GABA-ergic mechanisms and occur in cells expressing transcription factors STAT and SOCS which operate downstream from the cytokine, insulin and leptin signaling pathways. To test our hypotheses, we plan to investigate alterations in the central and peripheral cellular signaling relevant for the control of glucose metabolism in rats exposed to IH. In Specific Aim 1, we will determine whether exposure to IH for different periods causes progressive and regionally specific changes of mRNA and protein levels for transcription factors and receptors involved in central metabolic control (STAT, SOCS and insulin receptor substrates, leptin and adrenergic receptors, GABAA receptor subunits), and whether the changes persist following termination of IH. We will quantify mRNA changes at the regional level, study protein changes with immunohistochemistry, and obtain parallel measures of systemic alterations in glucose kinetics using the intravenous glucose tolerance test and minimal model analysis. In Specific Aim 2, we will determine whether, similar to its effect on the development of arterial hypertension, carotid body denervation prevents the development of diabetes-like changes. In Specific Aim 3, we will test whether acute local microinjections of adrenergic receptor agonists into distinct hypothalamic nuclei cause alterations in the expression of transcription factors and/or receptors similar to those induced by IH. In Specific Aim 4, we will test whether chronic local infusion or systemic treatment with adrenergic or angiotensin receptor antagonists prevent the IH-induced diabetes-like changes. The proposed experiments will provide a comprehensive assessment of the relationship between IH and the central mechanisms of insulin resistance, and evaluate the potential for therapeutic interventions. [unreadable] [unreadable]